About 2% of the human population is affected by various autoimmune diseases, including multiple sclerosis (MS). MS is neurodegenerative disease affecting the central nervous system (CNS) and leading to a progressive physical disability. Although the exact etiology and pathogenesis of MS is still obscure, it is believed that it might be autoimmune disease [1]. Histopathology of MS is characterized with demyelination of motor neurons in CNS, loss of oligodendrocytes and moderate inflammatory reaction. Affected areas in the brain are usually infiltrated with T-lymphocytes and macrophages. T-lymphocytes belong to the CD+ subtype and are characterized with increased production of Th1 cytokines (IL-2 and IFN-γ) [2]. As a result, the mononuclear cells are induced to produce increased amounts of some destructive substances such as lymphotoxines (LT) and tumor necrosis factor alpha (TNF-α). Many studies show that the abnormal production of IFN-γ plays a key role in the pathogenesis of MS [3-6].
Recombinant DNA technology reveals new approaches for neutralizing the activity of endogenous hIFN-γ to find application for treatment of autoimmune diseases including MS. An inhibitor of the hIFN-γ secretion is hIFN-β, which has already been applied for treatment of MS patients [U.S. Pat. No. 4,695,623, U.S. Pat. No. 4,897,471, WO9530435, CA2361081]. Patents RU2073522, RU2187332, RU02166959 recommend treatment with a mixture of hIFN-α, hIFN-β and hIFN-γ. It is reported, however, that the high daily doses of hIFN-β (8×106 IU) results in unfavorable consequences related with the following effects of hIFN-β: a) hIFN-β blocks the T-cells proliferation [7]; b) hIFN-β neutralizes IL-12 thus enhancing the effect of hIFN-γ on dendrite cells [8]; hIFN-β suppresses the activity of T cells, producing hIFN-γ and IL-4, thus lowering the level of CD4+ cells (Th1, Th2) and CD8+ (Tcl) cells without changing the ratio Th1/Th2 [9, 10]; d) after a short-term treatment of MS patients during the acute phase hIFN-β decreases the expression of pro-inflammatory cytokines (such as hIFN-γ and hIFN-α) and increases the expression of anti-inflammatory cytokines (IL-4 and IL-10) [11].
Another approach for healing MS patients consists in neutralizing the endogenous hIFN-γ by specific monoclonal antibodies [12, 13, W00145747]. The long-term treatment with anti-hIFN-γ antibodies, however, results in deterioration of the health conditions, probably because of weakening of the natural defense system.
U.S. Pat. No. 0,086,534 and CA2299361 offer a different approach for suppressing the abnormal production of IFN-γ based on the so called consensus interferons (IFN-con1, IFN-con2 and IFN-con3) belonging to the groups of hIFN-α, hIFN-β and hIFN-τ. These recombinant preparations, however, show side effects, including toxicity.
Proteins with amino acid sequence partly coinciding with that of the hIFN-γ have been applied as antiviral, antitumor and immunomodulating agents [U.S. Pat. No. 4,832,959, WO0208107, AT393,690]. Their effects, however, is hard to be assessed since the descriptions are not supported with experimental data.